DRUGS AREbeing discovered since the civilization of mankind. The folk-medicines were obtained from plants and were fortified by animal derived material or mineral which were discovered by experimentation and observation of human and animals response as these products were ingested.


Until 1800s old methodologies for drug discovery were used. Subsequently drug discovery and development started to follow the scientific techniques. More and more drugs have been discovered, tested and synthesised on a large scale.


Computers have revolutionised our daily life which has sped up the processing time of a calculation (so called job), a job that may be impossible to be done by human but computer is doing. It is being utilized in almost all fields from giant aeroplane to a tiny invisible robot. One of the most important uses is in the various phases of drug discovery and development. Drug discovery is a process of discovering new chemical molecules (either from natural or synthetic source) against a biological target molecule (DNA/RNA/Protein) that is up-regulated in a particular disease.


Various fields including pharmacy, bioinformatics, pharmacology and biotechnology are involved in the search of new medications. In 1970s computers were also integrated in the field of drug discovery and a new field so called Computer aided drug discovery (CADD) was emerged. CADD is a part of bioinformatics that uses the structural and functional information about the life-molecules in order to screen out the proper ligand against its target molecule. Recently CADD has contributed intensely in the design and discovery of novel drugs against many malicious diseases like malaria, hepatitis, HIV, tuberculosis using computational tools. These tools provide a virtual living system for a scientist to study the nature of bio-molecules and their interactions with other molecules in the biological system. The process of in silico (computer based) determination of molecular interactions is known as docking. Not confined to drug designing, but computers also helps scientists in predicting the structure and functions of newly identified sequences of DNA, RNA and proteins of unknown functions which can be used in drug designing subsequently.


Due to the tremendous efforts of physicists, mathematicians and computer scientists, the computational power is increasing exponentially that helps the chemists and biologists to solve the mysteries to several biological processes. By estimating the fundamental protein ligand interactions, now this is possible to predict the biological pathways that exist in the real biological world. The computer programmes use mathematical calculations (so called algorithms) in order to analyze the physical and chemical properties of atoms. Additionally the enhanced graphics of computers are making the use of computers more users friendly to determine the molecular structures.


After the automobile industries, the drug discovery is the most expensive field. On average the estimated cost of drug development is $0.8-1 billion from its concept to its availability in the commercial market. Furthermore, it is a laborious, risky and time consuming process. During last decades, a huge amount has been invested on drug discovery with least significant results. However, the increased computational power of CPU has led to improve the efficiency of drug development process. The CADD approach not only helps to reduce this cycle by 50 per cent but also beneficial in reducing the risk associated with this process. Advancements in combinatorial chemistry and virtual screening give better idea about the rapid synthesis and screening of chemical compounds.


Moreover CADD relies on different computational tools (computer programmes) and sources for the storage, management, analysis and modelling of compounds. Several molecular repositories and databases are building to assess lead molecules. The information regarding bio-molecules and the small drug like candidates has been increased dramatically, hence there is an urgent need for process that can accelerate the pace of drug discovery and should be cost effective. Many tools of CADD like molecular docking simulation, pharmacophore modelling, de novo drug design, molecular similarity calculation and structure or ligand-based virtual screening strategies are helpful to expedite this process.


To find a desire drug molecule out of million compounds is like finding a needle from the haystack that is impossible without the computer power. This mechanism is known as High Throughput Screening, started in early 90s. Alternatively, virtual screening, a computational technique is most widely used to screen proper molecules from a large compound databanks that are able to bind their biological target. Now-a-days, pharmaceutical companies use virtual screening to speed up the drug development process.


In 2009, “Nimbus Discovery” emerged from the collaboration of Schrödinger computational drug discovery software developer and capital firm Atlas Venture. Nimbus rose its funding to $24 million; in which Bill Gates was the main investor (www.nimbusdiscovery.com). Nimbus focuses on medically important and highly sought-after disease targets that have proven inaccessible to traditional industry approaches.


Information about the three dimensional structures of target molecules are mostly generated via X-ray crystallography and Nuclear Magnetic Resonance spectroscopy. Alternatively homology modelling, a computational technique so called homology modelling can be used for this purpose and have benefitted the scientist in the identification of several drug like molecules and de novo drug designing. Moreover many ligand based approaches like 3D-QSAR (Quantitative structure-activity relationship), pharmacophore modelling, and 2D or 3D similarity searching helps in the structural modification of existing drug molecules in order to improve their biological function. Computational tools also widely used to analyze and compare the sequences of biological targets for pathway analysis when no prior knowledge of the target structure is available.


In the past two decades, CADD approach has been widely used for screening drugs against major death-threat syndromes like HIV, HCV, Dengue virus, Malaria, Diabetes, Heart diseases and several malignant cancers. Many novel compounds were designed and screened using computer prior to their synthesis in test tubes and their efficacy were predicted. That approach resulted in the identification of several potent drug like compounds in appropriate time frame.


Many branches are evolved in CADD, including computational biology, computational chemistry, computational genomics, and computational toxicology. These techniques help in refining the molecular structures giving a greater drug activity and fewer side effects. It helps to assess the pharmacological properties of molecules like Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET properties). Once a numerable number of molecules are achieved the next step is to test them on animal models. Successfully tested molecules are taken for clinical trials. This process helps in checking side effects and setting human dosages.


Several databases of chemical compounds are freely available that can be used to search novel drug candidates. A researcher can download a chemical library for virtual screening using structure or ligand based drug design approach to search a molecule, a perfect ligand (ultimately a drug). These all molecules are purchasable, so, any lead molecule can be purchased and are delivered within a period of up to 10 weeks depending upon the availability.


In Pakistan many institutions are working on computational drug designing. The leading one is International Center for Chemical and Biological Sciences (ICCBS), University of Karachi. Moreover National University of Science and Technology, Centre of Excellence in Molecular Biology, International Islamic University Islamabad, COMSATS Institute of Information Technology, Abdul Wali Khan University Mardan, Khyber Medical University, Government College University Faisalabad, National Institute of Biotechnology and Genetic Engineering, National Center of Bioinformatics, and National Center of Proteomics also offers Bioinformatics courses and effectively involved in CADD research.


Thus computer – a great invention – is revolutionizing our health-care. In near future it will be using for generating personal drugs.


The writers are Computational Biologists at the National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore.